B-Cell-Mediated Strategies to Fight Chronic Allograft Rejection

Ali Dalloul

doi:10.3389/fimmu.2013.00444

Abstract

Solid organs have been transplanted for decades. Since the improvement in graft selection and in medical and surgical procedures, the likelihood of graft function after 1 year is now close to 90%. Nonetheless even well-matched recipients continue to need medications for the rest of their lives hence adverse side effects and enhanced morbidity. Understanding Immune rejection mechanisms, is of increasing importance since the greater use of living-unrelated donors and genetically unmatched individuals. Chronic rejection is devoted to T-cells, however the role of B-cells in rejection has been appreciated recently by the observation that B-cell depletion improve graft survival. By contrast however, B-cells can be beneficial to the grafted tissue. This protective effect is secondary to either the secretion of protective antibodies or the induction of B-cells that restrain excessive inflammatory responses, chiefly by local provision of IL-10, or inhibit effector T-cells by direct cellular interactions. As a proof of concept B-cell-mediated infectious transplantation tolerance could be achieved in animal models, and evidence emerged that the presence of such B-cells in transplanted patients correlate with a favorable outcome. Among these populations, regulatory B-cells constitute a recently described population. These cells may develop as a feedback mechanism to prevent uncontrolled reactivity to antigens and inflammatory stimuli. The difficult task for the clinician, is to quantify the respective ratios and functions of “tolerant” vs. effector B-cells within a transplanted organ, at a given time point in order to modulate B-cell-directed therapy. Several receptors at the B-cell membrane as well as signaling molecules, can now be targeted for this purpose. Understanding the temporal expansion of regulatory B-cells in grafted patients and the stimuli that activate them will help in the future to implement specific strategies aimed at fighting chronic allograft rejection.

Highlights

Kidneys have been the most frequently transplanted organs for decades
Chronic rejection is mediated by T-cells and often successfully prevented by immunosuppressive drugs aimed at inhibiting T-cell proliferation
The efficiency of Rituximab is a proof of concept for the role of B-cells in GVHD, the few studies conducted so far have shown limited effect in treating chronic kidney rejection Rituximab was even deleterious as an induction therapy for acute cellular rejection [18]. This suggested that B-cells may be protective in this setting, and strengthened the emerging concept that B-cells within the grafted tissue can be associated with tolerance rather than rejection [19]

Summary

INTRODUCTION

Kidneys have been the most frequently transplanted organs for decades. Since the improvements in graft selection and in medical and surgical procedures, the likelihood of graft function after 1 year is close to 90%. They are produced by T-dependent (TD) B2 B-cells with a highly diversified repertoire This is in contrast with preformed antibodies: anti-HLA Abs occur following multiple blood transfusions a condition frequently observed in patients on the waiting list for kidney transplantation. The efficiency of Rituximab is a proof of concept for the role of B-cells in GVHD, the few studies conducted so far have shown limited effect in treating chronic kidney rejection Rituximab was even deleterious as an induction therapy for acute cellular rejection [18] This suggested that B-cells may be protective in this setting, and strengthened the emerging concept that B-cells within the grafted tissue can be associated with tolerance rather than rejection [19].

Agonistic mAb

Findings

CONCLUSION